The development of an effective AIDS vaccine remains our best hope for controlling the HIV pandemic. Although several vaccine approaches are being tested for efficacy in the SIV/rhesus macaque model, the immunologic requirements of effective anti-HIV immunity remain largely unknown. In addition to induction of robust cellular and humoral immune responses, the quality of immunologic memory, and the efficiency of induction of mucosal T cell immunity are likely to be important factors determining the ability of a vaccine to protect against AIDS virus challenge. We are testing recombinant herpes simplex viruses (recHSV) expressing SIV proteins as candidate vaccines in the simian model of AIDS. Since herpesviruses induce persistent infection, we are investigating whether recHSV-SIV vaccines can match the protective efficacy of live attenuated SIV vaccines. Specific Aims will include: 1. To compare the immunogenicity and protective efficacy of different recHSV immunization regimens. 2. To investigate the relationship between the phenotype of vaccine-induced memory T lymphocytes and protection against SIV challenge. 3. To examine whether SIV-specific T lymphocytes are induced in the rectal mucosa following immunization with DNA/recHSV administered via systemic or mucosal routes. 4. To investigate whether pre-existing HSV immunity is a barrier to effective immunization with multiple gene depleted recHSV vectors.